Retinoids are a class of compounds structurally related to vitamin A, comprising natural and synthetic compounds, which have been found to be clinically useful in dermatological, oncological and immunological diseases.
The activity of retinoids is thought to be mediated by the nuclear retinoid receptors as for example the known retinoid receptors RARα, β, and γ or RXRα, β, and γ. The activity of the retinoids may be an agonistic or antagonistic activity. Retinoids with receptor agonistic activity bind and activate receptors, whereas retinoids with receptor antagonistic activity bind receptors but do not activate them.
Specific examples for retinoids, which have been found to be clinically useful, are for example all-trans retinoic acid which is known to be effective in the treatment of acne, 13-cis retinoic acid which can be used in severe cases of acne (see Römpps Chemie Lexikon, 1987) or 9-cis retinoic acid, 9-cis retinal and 9-cis retinol as well as derivatives thereof, which are said to be clinically efficacious in the treatment of T-helper cell type 1 mediated immune diseases (WO 99/09969).
The retinoids or pharmaceutically acceptable derivatives thereof can generally be administered either topically or systemically.
Oral pharmaceutical preparations of retinoids are known for example from EP-A-0 552 624 A1, WO 00/25772 and WO 99/24024, describing tablets, sachets, aerosols for inhalation, soft and hard gelatin capsules.
A preferred oral dosage form is a soft gelatin capsule, as this material is easily dissolved in the digestive tract. An overview on soft gelatin capsules is for example given in Soft Gelatin Capsules Development, Tabibi, S. E. and Gupta, S. L., Editor: Liu, Rong, Water-Insoluble Drug Formation (2000), pp. 609-633, Interpharm Press, Buffalo Grove, Ill., USA. Moreover, in general, these preparations are favoured as they disguise the unpleasant taste and obnoxious odours that may be associated with the active pharmaceutical ingredient itself. They may also protect the active ingredient from oxygen and light induced degradation.
EP-A-0 552 624 A1, for example, discloses a soft gelatin capsule with a fill mass formulation consisting of 5-50 mg 9-cis retinoic acid, 1-3 parts of oil, and 1-5 parts of a wax mixture.
Furthermore, WO 99/24024 discloses a specific retinoid-containing soft gelatin capsule preparation containing 20 mg of active retinoid compound, with 0.028 mg DL-α-tocopherol, 4.2 mg hydrogenated castor oil, 56.00 mg caprylic/capric/stearic triglycerides, and 199.772 mg medium chain triglycerides.
However, a crucial disadvantage of this formulation is that it exhibits very slow dissolution rates due to the formation of pellicles after long-term storage at temperatures above 5° C. This phenomenon increases with higher storage temperatures of the pharmaceutical preparation. Furthermore, in aqueous media, a non-dispersible fill mass and in some cases the formation of needles is observed.